Autonomic neuropathy is a significant diabetic complication resulting in increased patient morbidity and mortality. Our studies of the sympathetic nervous system of autopsied diabetic patients and several rat (STZ-diabetic, BBW) and mouse (STZ-diabetic, NOD) models of diabetic autonomic neuropathy we have developed have demonstrated close neuropathologic correspondence. The neuropathologic hallmark of diabetic sympathetic autonomic neuropathy is the occurrence of degenerating, regenerating, and distinctive dystrophic axons (neuroaxonal dystrophy, NAD) involving nerve terminals within prevertebral visceral sympathetic ganglia. In the last funding period we have shown that diabetic rat sympathetic ganglia are IGF-I deficient and have significant defects in PI3K/Akt signaling pathway intermediates which are reversed by treatment with exogenous rhIGF-l. Significantly, we have shown that 2 months of rhIGF treatment of chronically diabetic rats with established ganglionic NAD resulted in nearly complete reversal of NAD without altering the metabolic severity of diabetes, suggesting a role for IGF-I in its pathogenesis and therapy. The use of mutant transgenic mice with defects in neuronal IGF-I receptors (IGF-1R) or IGF-I production itself, as outlined in this proposal, will permit the critical analysis of the role of IGF-I in the pathogenesis and therapy of diabetic autonomic neuropathy. We will test the hypothesis that the molecular pathogenesis of diabetic autonomic neuropathy represents the effect of hyperglycemia superimposed on a defect in IGF-I action, resulting from decreased levels of circulating IGF-I, deficient autocrine production of IGF-I by sympathetic neurons themselves or decreased neuronal IGF-1R. We will determine if autoimmune IGF-I deprivation or pharmacologic inhibition of IGF-IR function will induce NAD in ZDF type 2 diabetic rats which are hyperglycemic but protected from NAD by increased serum IGF-I. We also propose that defective IGF-I signaling in sympathetic ganglia may be bypassed by the newly discovered neurotrophic effect of erythropoietin (EPO), an agent which influences the same ganglionic PI3K/Akt signaling pathway as IGF-I and is approved for patient use in chemotherapy. We have recently found that EPO given to diabetic mice results in dramatic prevention of NAD without changes in blood glucose levels. Thus, we are poised to understand the pathogenesis and develop novel therapies for diabetic autonomic neuropathy.